Jiajing, a cousin of the Zhengde Emperor, was made the new emperor as the puppet of Zhang Yong and the Eight Tigers. His disdain for the duties of an Emperor was perfect for the Tigers, as they would rule in his stead, making important decisions while he spent his time in brothels and private palaces.
In 1524, tired of the Chinese Assassins' meddling, the Eight Tigers triggered the Great Rites Controversy which led to Jiajing hunting down many officials to destroy all who opposed him. As a byproduct of this, the entire Chinese Assassin branch was almost eradicated, with only a few survivors fleeing west to seek support from other Assassins.
To prevent them from succeeding, Jiajing sent men after them, following the Assassins as far as Italy. In Venice, they killed the Chinese Assassin Mentor Zhu Jiuyuan, who was traveling with a female Assassin named Shao Jun, who managed to escape them. They followed her to Florence, where she sought aid from the former Mentor of the Italian Assassins, Ezio Auditore da Firenze, to learn how to rebuild the Chinese Brotherhood. Jiajing's men tracked the two to a marketplace in Florence while Ezio ran errands, and one of the men confronted them in an alley.
Shao fought and killed him, and both she and Ezio quickly fled, knowing more of Jiajing's men would most likely follow. On the carriage ride back to Ezio's home, Shao told him about Jiajing's cruel ways. She explained that Jiajing liked to inflict pain on his enemies with torturous deaths. Explaining that she had been a concubine before her mentor Wang Yangming had saved her, but when they returned to save the other concubines, Jiajing had killed them all via líng chí: a slow process of a thousand cuts until death.
Later that night, the rest of Jiajing's men faced both Ezio and Shao at Ezio's house. Most of the men employed Chinese sword-fighting techniques, but one of them instead used a Chinese hand cannon. Though they fought well, the men were all killed by the two Assassins. The next day, Shao departed for China, but not before receiving a mysterious gift from Ezio – a tiny chest, which he told her to only open if she lost her way.
From 1542 to 1550, Jiajing's empire was harassed by the Mongol leader Altan Khan. The Jiajing Emperor ended the conflict by offering the Mongol leader special trading rights. After the end of the conflict, the emperor expanded Peking by building the Outer City.
In his later years, Jiajing developed an interest in alchemy and immortality drugs. In 1567, the Assassins, playing on his desire to find the elixir of life, presented him with what they claimed was the miraculous concoction. The Emperor foolishly believed them and ingested the gift, which was actually concentrated mercury, and promptly succumbed to mercury poisoning. 
- A message that Clay Kaczmarek wrote in blood on the wall in Desmond Miles' room stated that "Within Emperor Jiajing's sin and Quetzalcoatl's hunger lies the answers."